1. Field
The present invention relates to various aspects of a novel process scheme for the preparation of acylated 1,3-dicarbonyl compounds, and in particular, to a process scheme for producing herbicidal acylated 1,3-dicarbonyl compounds, more particularly to methods for producing the selective herbicide mesotrione.
1. Related Art
2-[4-(methanesulfonyl)-2-nitrobenzoyl]cyclohexane-1,3-dione is a triketone having the common name ‘mesotrione’. Mesotrione is a herbicide having activity as a HPPD inhibitor. Formulations of mesotrione are known in the art and are commercially available.
Mesotrione has the following chemical structure:

Processes for the preparation of mesotrione are known in the art.
For example, U.S. Pat. No. 4,695,673 relates to various acylated 1,3-dicarbonyl compounds prepared by rearranging certain enol esters. These compounds include cyclohexanediones, where the acylating moiety is a benzoyl group which may be substituted with a wide range of different substituents. The enol rearrangement is carried out in the presence of a catalytic amount of a cyanide moiety, such as hydrogen cyanide, an alkaline earth metal cyanide, or a cyanide derivative, such as a cyanohydrin, and a molar excess of a moderate base, such as a trialkylamine, an alkali metal carbonate, or a corresponding phosphate.
U.S. Pat. No. 5,728,889 discloses a process for producing 2-(substituted benzoyl)-1,3-cyclohexanediones that does not require cyanide anion to effect the enol ester rearrangement. The process employs a reaction medium containing a base, such as a trialkylamine, an alkali metal carbonate, or a phosphate, and a polar aprotic solvent, such as dimethylformamide, that is substantially free of hydrogen cyanide or a cyanide anion.
U.S. Pat. No. 5,912,207 relates to transition metal chelates of herbicidal dione compounds, such as mesotrione, which are prepared by adding an aqueous solution of a transition metal ion to the dione compound in water or an organic solvent.
EP 0 805 792 discloses a process for the preparation of 2-(substituted benzoyl)-1,3 cyclohexanediones. The process employs a rearrangement reaction to form the desired 2-(substituted benzoyl)-1,3 cyclohexanedione, in the presence of a non-polar solvent, a cyanide source, an alkali or alkaline earth metal carbonate, a phase transfer catalyst and water.
EP 1 034 159 discloses a process for the preparation of acylated cyclic 1,3-dicarbonyl compounds, including mesotrione. This process also employs a rearrangement reaction and is conducted in a polar aprotic, dipolar aprotic or aromatic hydrocarbon solvent and in the presence of a moderate base and a defined azole compound, for example 1,2,4-triazoles and related analogues. In the case of mesotrione, 1-(2-nitro-4-methanesulphonylbenzoyl)-1,2,4-triazole is reacted with cyclohexan-1,3-dione in the presence of potassium carbonate suspended in acetonitrile. Acetontrile is removed from the resulting mixture under reduced pressure, the residue dissolved in water and acidified with hydrogen chloride solution. The solution is then extracted with dichloromethane, dried, filtered and the solvent removed under reduced pressure.
Attention has also been paid in the prior art to processes preparing mesotrione and similar compounds in a purer form.
For example, EP 1 377 544 discloses a process for the purification of 2-nitro-4-methylsulfonylbenzoic acid (NMSBA), an intermediate of use in the preparation of mesotrione. The process comprises, in order, dissolving NMSBA in water at a pH of 2 to 10, followed by filtration, optionally contacting the solution of NMSBA with activated carbon at a pH of from 2 to 10; treating the aqueous solution of NMSBA with sufficient base to hydrolyse undesired nitro and dinitro substituted impurities; followed by maintaining the resulting aqueous solution of NMSBA at a temperature of up to 95° C. and adjusting the pH of the solution to a pH sufficient to effect crystallization of NMSBA upon cooling.
A process for the purification of mesotrione is disclosed in EP 1 740 534. The process is aimed at reducing the cyanide levels in a mesotrione sample, arising from the use of acetone cyanohydrin as a catalyst in the rearrangement reaction forming mesotrione. The process disclosed comprises forming an aqueous solution of mesotrione, adjusting the pH of the solution to a value of 9.5 or higher, and crystallising mesotrione out of solution.
Further, WO 2005/035487 discloses a process for purifying mesotrione. The process comprises the steps of forming an aqueous mesotrione enolate solution, performing one ore more purification processes on the solution, and thereafter crystallising the purified mesotrione from the aqueous solution.
The enolate solution may be formed by the addition of an appropriate base. A pH of from 6 to 13 is maintained when forming the enolate solution. However, the teaching of WO 2005/035487 is that strong bases must be used in order to attain alkaline conditions having high pH values in the range of from 9.5 to 13. Values of pH in this range are used in all the specific examples of WO 2005/035487. Suitable purification processes are filtration or adsorption with a suitable sorbent, followed by extraction and decantation using an organic solvent.
WO 2007/083242 discloses a process for the cyrstallization of mesotrione. The process comprises introducing an aqueous solution of mesotrione into a crystallizer. Seed crystals are added to the crystallizer to seed the crystal growth. The seed crystals are predominantly of the Form I polymorph. The aforementioned process is also described as being of use for converting the Form II polymorph of mesotrione to the more stable Form I polymorph, by way of crystallization.
WO 2006/021743 discloses a process for the preparation of polymorphs of mesotrione. The process employs crystallization of mesotrione. Control of the pH of the solution during crystallization is said in WO 2006/021743 to allow the Forms I or II of mesotrione to be selectively obtained.